Over the last two decades, staphylococci have become important causes of infection in hospitalized patients. Because of their high prevalence on the skin, staphylococci are ideally situated to cause serious infections in debilitated or immunosuppressed patients. The staphylococcal species most frequently pathogenic in humans are Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE). Both groups have developed resistance to multiple antibiotics making antimicrobial therapy difficult. In recent years SE has become a major cause of nosocomial infection in patients whose treatments include the placement of foreign materials such as cerebrospinal fluid shunts, vascular catheters or joint prostheses. SE is a common cause of post operative wound infections peritonitis in patients with continuous ambulatory peritoneal dialysis. Patients with impaired immunity (malignancy, bone marrow transplant) or those receiving parenteral nutrition through central venous catheter are also at high risk for developing SE sepsis (Patrick, J. Pediat., 1990).
SE has emerged as a common cause of neonatal nosocomial sepsis in premature infants. As shown by Fleer and colleagues, (Pediatr Infect Dis, 1983) SE infections frequently occur in immature babies that have received parenteral nutrition. Premature babies have impaired immunity with deficiencies in antibodies, complement and neutrophil function. Lipid infusion is now a standard ingredient of parenteral nutrition therapy in many nurseries and may further impair immunity to bacterial infection as disclosed by Fischer and colleagues (Lancet, 1980; 2:819-20). Recent studies have associated coagulase negative staphylococcal bacteria in neonates with lipid emulsion infusion (Freeman and colleagues, N. Engl. J. Mod, 1990). Further studies by Fleer and colleagues (J Inf Dis, 1985) showed that neonates had low levels of opsonic antibody to SE despite the fact that the sera had clearly detectable levels of IgG antibodies to SE peptidoglycan (opsonic antibodies for staphylococcus have been considered to be directed to the poptidoglycan antigens). While these studies suggested that neonatal susceptibility to SE might be related to impaired oposonic activity, it is not clear if antibodies directed against SE are opsonic or would be capable of providing protection when given passively to neonates. Further, it is unknown whether the presence of intralipid, which further impairs phagocytosis and killing of bacteria by phagocytes, would inhibit the activity of antibody.
The opsonic activity of pooled human immunoglobulin for SE was studied by Clark and colleagues (J Mod Microbiol, 1986), and showed that complement and IgG were both critical for efficient opsonization of SE. They noted, however, that in some studies complement was not required and that contrary to the report of Fleer (1985), absorption of serum with peptidoglycan may remove the opsonic activity for SE. Further studies by Clark and Easmon (1986) showed that several lots of standard intravenous immune globulin (IVIG) had variable opsonic activity for SE. One third of the IVIG lots had poor opsonization with complement and only 2 of 14 were opsonic without complement. Despite the fact that the IVIG lots are made from large plasma donor pools good opsonic antibody to SE was not uniformly present. Their studios focused on potential use of immunoglobulin to boost peritoneal defenses in patients receiving continuous ambulatory peritoneal dialysis and did not examine whether IVIG could be utilized for the prevention or treatment of bacterial sepsis, or the use of antibody to prevent or treat sepsis and lethal infection in immature or immunosuppressed patients and Specifically, no in vivo studies were done to test antibody to prevent or treat SE. There is no evidence therefore that the antibody would provide beneficial therapy in a setting of immaturity or impaired immunity.
The opsonic assays, that are currently used are slow and cumbersome for screening blood, plasma or immune globulin for antibodies to SE. It would be important to have a rapid antigen binding assay to screen for SE antibody, if that assay further correlated with opsonic activity in vitro and protection in vivo.
In order to determine if IgG is capable of enhancing protection against SE, a suitable animal model that is comparable to patients with SE infections is required. This is critical since neonates have low levels of complement and impaired neutrophil and macrophage function. While opsonic activity of immune globulin may be adequate under optimal conditions in vitro, protection may not occur in patients with immature or impaired immune systems. As has been demonstrated by Clark and colleagues (J Clin Pathol, 1986), most IVIG preparations were not opsonic when complement was removed. However, since SE has low virulence, suitable animal models of SE sepsis have not been available.
Yoshida and collegues, (J Microbiol, 1976) reported on a virulent strain of SE that infected mature mice with 90-100% of mice dying within 24-48 hours. This model is very different from that seen in patients and may represent an unusual type of SE infection. When they analyzed 80 fresh isolates of SE from humans, they were not able to kill mice. Non-human antibody to a now SE surface polysaccharide protected the mice from the virulent SE strain. A later report by Yoshlida and colleagues (J Med Microbiol, 1977) confirmed their previous observations. Passive prophylaxis with immunization induced non-human antibody showed that the IgG fraction did not protect while the IgM fraction did provide protection. Thus demonstrating in this model that IgG antibody was not protective. As noted previously herein neonates had good levels of IgG to SE, but had low levels of opsonic antibody (Fleer and colleagues, J. Infect. Dis, 1985), consistent with the findings in this study and showing that the role of IgG in protection against SE is unclear. In 1987 the report by Ichiman and colleagues (J Appl Bacteriol, 1987) extended their animal studies to include analysis of protective antibodies in human serum against their selected virulent strains of SE. Protective antibody was found in the IgA, IgM and IgG immunoglobulin fractions. These studies are in conflict with their previous data showing that IgG was not protective and fails to establish a definitive role for any of the immunoglobulin classes (IgG, IgM or IgA).
In the animal model described by Yoshida, Ichiman and colleague mature, non-immunosuppressed mice were used and death was considered to be related to toxins not sepsis (Yoshida and colleagues, J. Microbiol, 1976). Most clinical isolates did not cause lethal infections in their model. Since quantitative blood cultures were not done, it is not known whether antibody would prevent or treat SE sepsis in immature immunosupressed patients or specifically in the presence of intralipid.
Antibody provides protection in humans against certain encapsulated bacteria such as Hemophilus influenzae and Streptococcus pneumoniae. Individuals such as young infants who are deficient in antibody are susceptible to infections with these bacteria and bacteremia and sepsis are common. When antibody to these bacteria is present it provides protection by promoting clearance of the bacteria from the blood. Immunoglobulin with antibody to H. influenzae and S. pneumoniae protects infants from sepsis with these bacteria. The article by Espersen and colleagues, (Arch Intern Mod, 1987) discloses the use of an antigen binding RIA assay to analyze IgG antibody to SE in patients with uncomplicated bacteremia and those with bacteremia and endocarditis. This assay used an ultrasonic extract of SE to identify SE specific Iga (the surface antigen in this study differs from the antigen used by Yoshida and colleagues which was obtained by a different method; gentle sonic oscillation). None of the patients with uncomplicated bactermia had IgG antibodies to SE. These data would suggest that IgG is unnecessary for effective eradication of SE from the blood. In addition, 89% of bacteremic patients with endocarditis developed high levels of IgG to SE. In these patients, IgG was not protective since high levels of IgG antibody (which may have developed late) were associated with serious bacteremia add endocarditis. Based on these studies the protective role of IgG in SE sepsis and indocarditis is not established, especially in the presence of immaturity, debilitation, intralipid infusion, or immunosuppresion. In addition, the extensive review of Patrick et al. (J. Pediat., 1990) does not include immunoglobulin as a potential prophylactic or therapeutic agent for SE infections.
It has been recognized by the medical community that SE is an important pathogen in certain high risk individuals, such as patients with foreign body implants, premature neonates and immunosuppressed patients. Accordingly there is a need for a human immune globulin that would prevent or treat SE infections such as, sepsis or endocarditis and promote clearance of SE from the blood of such high risk people.